Essentials of Sepsis

Management
John M. Green, MD

KEYWORDS
 Sepsis  Sepsis syndrome  Surgical infection  Septic shock
 Goal-directed therapy

KEY POINTS
 Successful treatment of perioperative sepsis relies on the early recognition, diagnosis,
and aggressive treatment of the underlying infection; delay in resuscitation, source
control, or antimicrobial therapy can lead to increased morbidity and mortality.
 When sepsis is suspected, appropriate cultures should be obtained immediately so that
antimicrobial therapy is not delayed; initiation of diagnostic tests, resuscitative measures,
and therapeutic interventions should otherwise occur concomitantly to ensure the best
outcome.
 Early, aggressive, invasive monitoring is appropriate to ensure adequate resuscitation and
to observe the response to therapy.
 Any patient suspected of having sepsis should be in a location where adequate resources
can be provided.

INTRODUCTION

Sepsis is among the most common conditions encountered in critical care, and septic
shock is one of the leading causes of morbidity and mortality in the intensive care unit
(ICU). Indeed, sepsis is among the 10 most common causes of death in the United
States.1 Martin and colleagues2 showed that surgical patients account for nearly
one-third of sepsis cases in the United States. Despite advanced knowledge in the
field, sepsis remains a common threat to life in the perioperative period. Survival relies
on early recognition and timely targeted correction of the syndrome’s root cause as
well as ongoing organ support. The objective of this article is to review strategies
for detection and timely management of sepsis in the perioperative surgical patient.
A comprehensive review of the molecular and cellular mechanisms of organ dysfunc-
tion and sepsis management is beyond the scope of this article. The information pre-
sented herein is divided into sections devoted to definitions and diagnosis, source

The author has nothing to disclose.

Department of Surgery, Carolinas Medical Center, 1000 Blythe Boulevard, Suite 601, Charlotte,
NC 28203, USA
E-mail address: john.m.green@carolinashealthcare.org

Surg Clin N Am 95 (2015) 355–365

http://dx.doi.org/10.1016/j.suc.2014.10.006 surgical.theclinics.com
0039-6109/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
356 Green

control, fluid therapy, antibiotic therapy, and organ support for clarity of discussion,
but the practitioner should understand that these approaches occur simultaneously
at the bedside, and each action is related to, and should act in concert with, the others.

DEFINITION AND DIAGNOSIS

The most important aspect of intervention in sepsis is early recognition of the signs
and symptoms of the condition. Reducing time to diagnosis and initiation of therapy
for severe sepsis is considered a critical component of mortality reduction.3 The
Society of Critical Care Medicine and the American College of Chest Physicians
proposed standard definitions of this illness spectrum in a consensus published in
1992. The systemic inflammatory response syndrome describes an immune response
consisting of 2 or more of the following:
 Temperature greater than 38 C or less than 35 C
 Heart rate greater than 90 beats per minute
 Respiratory rate higher than 20 breaths per minute or a PaCO2 below 32 mm Hg
 Leukocytosis of 12,000/mm3 or less than 4000/mm3
This inflammatory reaction in the presence of infection is known as sepsis. Compli-
cations of organ failure and hypotension constitute severe sepsis. Finally, septic shock
is defined by severe sepsis accompanied by hypoperfusion and organ failure refrac-
tory to fluid resuscitation.4
As with all clinical maladies, a focused history and physical examination can provide
vital information about potential risk factors for infection and the most likely site of
origin. Several clinical clues may support the clinician’s suspicion of infection. For
example, unexplained tachycardia is frequently the first indicator of inadequate organ
perfusion or a hyperdynamic state of inflammation and should be thoroughly investi-
gated in a perioperative patient. Septic patients, unlike those in cardiac failure or
hemorrhagic shock, frequently have warm skin on examination because their periph-
eral vasculature is not constricted. Acute glucose elevation can be a predictor of infec-
tion and should raise the provider’s suspicion when present.5 Inadequate urine output,
while useful in monitoring volume and perfusion status, is a late finding in sepsis and
septic shock.
Sepsis in the surgical patient is likely an underappreciated cause of morbidity and
mortality in the perioperative period. In the postoperative period beyond 24 hours,
sepsis is by far the most common cause of shock. Sources include surgical site infec-
tions, catheter-related bloodstream infections (CRBSI), pneumonia, and urinary tract
infections. Moore and colleagues6 found that the abdomen was the most common
site of infection in their general surgery ICU population, accounting for 63% of cases,
followed by the lungs (17%), wound/soft tissue (10%), urinary tract (7%), and all other
sites (4%). In fact, the authors demonstrated that the incidence of sepsis and septic
shock exceeded those of pulmonary embolism and myocardial infarction by
10-fold. Gram-negative species were the most prevalent culprits, particularly in
abdominal sources of sepsis.6 An understanding of the patient’s recent clinical trajec-
tory is invaluable, particularly in the perioperative period. Host defense mechanisms
can be compromised by many factors, including surgery, implanted devices, or previ-
ous antibiotic use. Knowledge of the patient’s surgical history can give clues to mental
status changes, increased minute ventilation, decreased urine output, glucose intoler-
ance, thrombocytopenia, or gastrointestinal failure.
Appropriate cultures should be obtained before initiating antimicrobial therapy,
provided the antimicrobials are not delayed. These cultures should include one set
 Essentials of Sepsis Management 357

of blood cultures drawn from any indwelling device, and a separate set drawn periph-
erally. If the site of origin is not clear, prompt imaging studies should be performed, as
required, to investigate suspected sources of infection, and any potential source
should be sampled.
Any patient suspected of being in septic shock should be immediately moved to the
ICU and administered antibiotics within 1 hour. Septic shock, a result of infection and
the attendant inflammatory response, is composed of metabolic derangements attrib-
utable to inadequate perfusion, resulting in the buildup of lactic acid and the disruption
of normal cellular function. However, the other significant challenge of the shock
syndrome consists of the organism’s neuroendocrine responses aimed at restoring
adequate perfusion. One of these responses, glucose dysregulation, is a common
clue to the presence of an infectious source. One prospective study of 2200 trauma
patients admitted to the ICU revealed a 91% positive predictive value of acute glucose
elevation in the diagnosis of infection.5 This stress-induced hyperglycemia is generally
seen as a transient plasma glucose level greater than 200 mg/dL and is thought to
occur following increases in cortisol, glucagon, and epinephrine. Acute glucose eleva-
tion should stimulate clinicians to search for a new source of infection.
When septic shock is diagnosed, fluid bolus should be given, unless there is indis-
putable evidence of acute left heart failure. Electrocardiogram tracing should be
obtained immediately to determine the likelihood of cardiac dysfunction. Arterial blood
gas should be measured, as pH will drop below neutral due to anaerobic metabolism
and lactic acid accumulation, if a shock state exists.
After the syndrome is recognized and resuscitation is begun, a review of the
patient’s medical history is paramount to determine causation. Surgical sites must
be quickly examined for erythema, drainage, bullous changes, or other signs of infec-
tion. Surgeons and those caring for surgical patients should have specific knowledge
of any operative procedure a patient has undergone, because this will surely help them
focus on possible causes for sepsis and septic shock. If sepsis occurs in the first
24 hours after surgery, surgical site infection should be entertained. A streptococcal
wound infection can quickly progress to myofascial necrosis. If this is present, radical
debridement in the operating room is mandatory, supported by antibiotic therapy.

SOURCE CONTROL

A specific, treatable source of sepsis should always be aggressively sought and

addressed as rapidly as possible. Specifically, abscess drainage, wound exploration,
debridement of necrotic tissue, removal of infected implanted device, or surgical
control of infectious source should occur simultaneously with resuscitation and anti-
biotic administration. An identified source should always be sampled and cultured
for targeted therapy. A rare exception for surgical intervention exists with pancreatic
necrosis, in which delayed surgical intervention has been shown to produce better
outcomes.7 Without adequate source control, resuscitative efforts will not be success-
ful. Definitive operation in the case of abdominal sepsis is not as important as limiting
the ongoing physiologic insult. A damage-control approach is appropriate for septic
shock from abdominal sources using the same principles as the damage-control
approach to trauma care.8

FLUID THERAPY AND HEMODYNAMIC SUPPORT

The ultimate goal of any hemodynamic intervention is the improvement of tissue perfu-
sion and oxygenation. Subtle changes in a patient’s condition are valuable signs in
early recognition of hypoxemia or acidosis. Adequate fluid resuscitation should ideally
358 Green

be achieved before the use of vasopressors, although these are sometimes necessary
earlier in severe cases. Initial fluid resuscitation should consist of crystalloid resusci-
tation of 30 mL/kg per ideal body weight. Patients with evidence of tissue hypoperfu-
sion after initial fluid challenge, or those with persistent blood lactate concentration of
4 mmol/L or less, should receive ongoing, protocolized resuscitation. Evidence of
hypoperfusion can appear in many ways, and treatment requires the physician to
be at the bedside observing the effects of current therapy. Patients with early sepsis,
whose vital signs may still fall within an expected range, might display metabolic
derangements, such as confusion, a change in their state of wakefulness, or
decreased urine output. If raising the blood pressure with volume or vasopressors
mitigates these derangements, then central nervous system responsiveness or urine
volume can be a good indicator of the adequacy of tissue perfusion.9
The Surviving Sepsis Campaign (SSC) suggests goals of this resuscitation are
central venous pressure of 8 to 12 mm Hg, mean arterial pressure (MAP) of 65 mm
Hg or more, urine output of 0.5 mL/kg/h or more, mixed venous oxygen saturation
of at least 65%, or superior vena cava oxygen saturation of 70% (grade 1C recom-
mendation).10 A randomized controlled trial targeting these goals in the initial 6-hour
period demonstrated a 15.9% reduction in 28-day mortality. This strategy was termed
early goal-directed therapy.11 Although the SSC demonstrated that adherence to fluid
resuscitation targets was low, the goals remain a strong recommendation endorsed
by the SSC.12 Further study has determined goal-directed therapy is both clinically
sound and economically beneficial.13
No clear benefit has been shown from the use of colloid solution over crystalloid in
resuscitation for sepsis. A low-level recommendation comes from the SSC for the
consideration of albumin in severe sepsis and septic shock.10 The SAFE trial showed
albumin to be as safe and effective as normal saline.14 In a meta-analysis of 17
randomized trials, albumin administration showed small and variable benefit across
different protocols. Although its use remains controversial, it can be considered in
severe sepsis and septic shock in patients who have received large-volume crystalloid
resuscitation.
Commonly, patients in septic shock decompensate to a point whereby their endog-
enous mechanisms can no longer maintain adequate oxygen delivery. In refractory
shock, vasopressors are desirable aids to help compensate for distributive shock. If
vasopressors are needed to reach the target of MAP of 65 or greater, norepinephrine
is the first choice with strong a-1 and b-1 characteristics, and epinephrine may be
added. Vasopressin (0.03 U/min) may be combined with norepinephrine but should
not be used as the initial medication.10,15 Clinicians must be aware, however, that
these vasopressors are associated with serious adverse events, including dysrhyth-
mias, chest pain, myocardial infarction, limb ischemia, mesenteric ischemia, and
stroke. Patients who have such adverse events may also have significantly increased
mortality.16
Phenylephrine is not recommended for use in septic shock unless norepinephrine is
associated with severe dysrhythmia or as salvage therapy when other vasopressors
have failed to achieve the target MAP.17 Low-dose dopamine is not recommended
for the purpose of maintaining renal function.18 In the setting of myocardial dysfunction
or ongoing hypoperfusion, despite intravascular volume replacement and adequate
MAP, dobutamine should be considered at a rate up to 20 mm/kg/min.
Measurement of blood flow and intravascular volume status at the bedside can be
assisted with multiple available technologies.19 The use of these tools requires knowl-
edge of their methods and limitations, however, so the data they generate can be
correctly interpreted. The efficacy of these monitoring technologies requires further
 Essentials of Sepsis Management 359

study before these tools are deemed standard of care in sepsis management. An arte-
rial catheter for monitoring and continuous analysis should be placed in any patient
requiring vasopressors and aggressive blood pressure management. Pulmonary
artery catheters, while used much less frequently than in past decades, may still be
considered in shock management. A large meta-analysis of randomized controlled
trials concluded that use of a pulmonary artery catheter did not increase overall
mortality or days in the hospital, nor did it confer any other benefit.20 Use of these tech-
nologies is based on clinician judgment and experience in interpreting data. Ulti-
mately, the goal remains the same: to restore circulation to a normal state and
reverse hypoperfusion while inflicting no further harm on the patient.
If hemodynamic targets can be met and perfusion restored with volume and vaso-
pressors, additional corticosteroids provide no real benefit.10 However, there may be a
role for hydrocortisone supplementation in refractory hypotension, dosed at 200 mg
per day. The CORTICUS trial, a large European multicenter trial, failed to show benefit
from steroid therapy in patients with septic shock, although it included patients
whether or not they were responsive to vasopressors.21 Several other randomized
trials have shown significant shock reversal with steroid therapy.22–25 Random cortisol
levels and adrenocorticotropic hormone stimulation testing have not been demon-
strated to be useful or predictive of patients who will benefit from steroid
supplementation.21,22

ANTIMICROBIAL THERAPY

The timely administration of appropriate antimicrobials is critically important to reduce

morbidity and mortality from sepsis.26–29 The choice of agents is based on multiple
factors, including patient history, details and timing of surgical procedures, previous
antibiotic exposure, and hospital antimicrobial susceptibility patterns. Cultures of
blood, urine, pulmonary secretions, wound drainage, or other potential infectious sites
should be performed before initiation of antibiotics. Broad-spectrum antimicrobial
therapy should begin within 1 hour of recognizing the presence of severe sepsis or
septic shock.10
The initiation of broad-spectrum antibiotics, meant to cover a host of possible
culprit organisms, should be able to contain the most common infectious agents in
a given hospital or ICU and be effective at limiting superinfection and resistant organ-
isms. The prevalence of methicillin-resistant Staphylococcus aureus should be
considered, and initial antimicrobial therapy should include agents active against
this strain. In addition, antifungal therapy should be considered if candidemia is a likely
pathogen. Recent Infectious Diseases Society of America guidelines recommend anti-
fungal therapy in immunosuppressed or neutropenic patients, those who have
received prior antibiotic therapy, or those who have fungal colonization.30 Combina-
tion therapy including an extended-spectrum b-lactam and an aminoglycoside or
fluoroquinolone should be used if complicated or multidrug-resistant infections such
as Acinetobacter and Pseudomonas species are suspected.10 Combination therapy
for suspected or known Pseudomonas aeruginosa or other multidrug-resistant
gram-negative pathogens increases the likelihood that at least one agent will be
effective.31
Daily assessments of the antibiotic regimen should examine clinical progress of the
patient, culture data to guide de-escalation of the broad-spectrum regimen and target
specific culprit organisms as soon as they are known, and compliance with antibiotic
stewardship guidelines to ensure appropriate combinations and length of therapy.
Such stewardship programs are in place to prevent resistance, reduce toxicity, and
360 Green

reduce costs.10 Once the causative pathogen is identified, the most appropriate and
cost-effective regimen should be implemented. This practice reduces the likelihood of
superinfection with opportunistic organisms such as Candida species, Clostridium
difficile, or vancomycin-resistant Enterococcus species, which can all be sources of
septic shock and subsequent mortality. Once started, antimicrobial therapy should
generally not exceed 7 to 10 days. Certainly, variables exist that necessitate longer
therapy including certain patient factors relating to response and immune susceptibil-
ity, undrained foci of infection, and some fungal infections.
A common challenge in critical care is determining when to stop antibiotics. Occa-
sionally, patients appear septic, and broad-spectrum antibiotics are initiated, but cul-
ture data never identify causative pathogens. Clinicians are then presented with the
conundrum of continuing antibiotics in a patient who might be clinically improving,
although there is no specific infection identified, or stopping the regimen to prevent
opportunistic infection, resistance, and wasted resources. Multidrug resistance
increases the cost of antimicrobial treatment by as much as 50%.32 The use of
biomarkers such as C-reactive protein and procalcitonin to differentiate between
infection and inflammation without an infectious source remains undefined.33 Procal-
citonin levels might aid in the decision to discontinue antibiotics in this scenario,
although available evidence remains conflicting.33–35 Clinicians should recognize
that even though bacterial and fungal sources are likely, blood cultures may be nega-
tive in as many as half the cases of severe sepsis if empiric therapy is administered.10
The decision to continue, narrow, or stop antimicrobial therapy is made on clinician
judgment with available information. Antimicrobial agents should not be used in states
of severe inflammation determined to be of noninfectious cause.
Clinicians should also consider sepsis of viral origin, and antivirals should be initi-
ated similar to antimicrobials. Viruses such as influenza, cytomegalovirus, and other
herpes viruses can all induce septic shock and should be considered in cases with
no clear bacterial infection. The role of some viruses in sepsis remains unclear, and
active viremia may act as a marker of disease severity rather than an actual agent
of organ injury and death in septic patients.36

ORGAN SUPPORT AND MONITORING

A comprehensive discussion of the mechanism and therapies for shock is beyond the
scope of this review, but the practitioner’s understanding of the essentials of manag-
ing septic shock is critical to patient survival. Knowledge of the shock syndrome has
increased dramatically over the past several decades, and all advances point to the
goal of prompt restoration of oxygen delivery. Invasive devices such as arterial blood
pressure monitors, central venous catheters, and urinary catheters are helpful to guide
therapy, although their placement should not detract from focusing on ongoing resus-
citation of the patient.
Tachypnea is common in the septic patient, as is mental status deterioration. Intu-
bation and mechanical ventilation might be warranted, depending on clinical findings.
Resuscitation should be ongoing while intubation is performed. Ventilation strategies
should be based on lung-protective strategies that have been supported by clinical
trials and widely accepted. The precise choice of ventilator mode and tidal volume
varies according to degree of respiratory distress and hypoxemia, sedation required,
volume status, and other factors that make ventilator support in the septic patient a
dynamic and individualized process. Positive end-expiratory pressure, recruitment
maneuvers for hypoxemia due to acute respiratory distress syndrome (ARDS), and
prone positioning in sepsis-induced ARDS with PaO2/FiO2 ratio less than or equal to
 Essentials of Sepsis Management 361

100 are all available adjunctive tools to improve oxygenation in the septic patient.
Rescue therapies such as high-frequency oscillatory ventilation, airway pressure
release ventilation, and extracorporeal membrane oxygenation require experienced
personnel with significant expertise.37
Although the optimum hemoglobin concentration in sepsis is not defined, red blood
cell transfusion is an important tool in organ support. The American College of Critical
Care Medicine Taskforce of the Society of Critical Care Medicine and the Canadian
Critical Care Trials Group endorse evidence-based transfusion for hemoglobin
concentration less than 7 g/dL.38,39 In patients with ongoing myocardial ischemia,
hemorrhage, ischemic coronary disease, or other comorbidities, this transfusion
trigger may be altered based on clinician judgment.
Immediately available indicators of global tissue perfusion include arterial pH and
lactic acid. These indicators of the metabolic state are important, and mortality is as
high as 46.1% in patients with both hypotension and lactate greater than 4.12 Once
resuscitation has restored adequate oxygen delivery, lactate should be metabolized
and pH should return to normal. Persistent acidosis indicates inadequate source
control such as ongoing bleeding or tissue necrosis. Lactic acid can be used as a
marker of hypoperfusion and the depth of the shock state.

NUTRITION AND GLUCOSE CONTROL

Nutrition management in critically ill patients is an important and frequently overlooked

aspect of care. Nutrition strategies that take into account information specific to the
patient’s perioperative condition, first-hand knowledge of the patient’s operative
history, and available nutritional access and support options should be in place. It is
preferable that patients be fed enterally, which can be accomplished orally or via
gastric or enteric feeding tube. If enteral feeding is not possible, total parenteral nutri-
tion can be instituted per hospital protocols. Nutrition is frequently withheld in the peri-
operative period because of ileus and intestinal surgery, among other reasons. No
direct evidence defines benefit or harm of parenteral nutrition in the first 48 hours in
sepsis.10 An adjunct to nutritional regimens is stress-ulcer prophylaxis. Patients with
severe sepsis or septic shock who have bleeding risk factors should be placed on
H2-blocker or proton pump inhibitor. Patients who are not coagulopathic, do not
require mechanical ventilation for at least 48 hours, and are normotensive do not
require stress-ulcer prophylaxis.10 In addition, those receiving enteral nutrition do
not need prophylaxis, and some evidence suggests that ulcer prophylaxis in this group
might increase the risk of pneumonia and death.40
Glucose regulation can be a challenge in the perioperative period when nutrition is
variable, and an infection state complicates this further. The largest study to date
addressing glucose control in ICU patients is the NICE-SUGAR trial, which used a
glucose level of 180 mg/dL as the upper limit of control. Multiple consensus state-
ments for glycemic control in hospitalized patients have emerged, generally targeting
levels between 140 and 180 g/dL.41–43 Goals should be within this range, and efforts
should be made to avoid wide swings in glucose levels. Of note, clinicians should
adjust insulin regimens when nutrition is withheld or discontinued, because this is a
common risk factor for hypoglycemia and there are large variations in glucose levels.

SPECIFIC PERIOPERATIVE ISSUES

Surgeons and those caring for surgical patients such as rapid response teams or crit-
ical care support teams should be aware of hospital protocols for resuscitation of
acutely ill patients. Patients in the perioperative period frequently require pain control,
362 Green

and many agents can suppress respiratory drive if not closely monitored. Drug inter-
actions can cause delirium, hypoxemia, tachycardia, and other signs similar to early
sepsis that must be detected and treated appropriately to rescue patients from poten-
tial decline.
Septic patients are at increased risk for deep venous thrombosis. Patients with sepsis
need daily venous thromboembolism prophylaxis, usually with daily low-molecular-
weight heparin unless there is a contraindication to heparin use. Consequences of
pulmonary embolism, particularly if a septic patient is already hemodynamically
compromised, can be fatal.

NOSOCOMIAL SEPSIS PREVENTION

Prevention of secondary sepsis remains an important goal in surgical critical care. The
nosocomial contributors of in-hospital sepsis are widely known but still poorly
controlled. Rigorous infection control practices, as recommended by the SSC, should
be enforced in any health care environment.44 Multiple well-designed studies have
demonstrated efficacy of focused interventions to reduce nosocomial infections.45,46
Many health care facilities have specific policies to reduce nosocomial infection, which
should be strictly followed by all who enter patient care areas, including family
members and visitors, although they are frequently not required to do so.
Ninety percent of nosocomial sepsis cases are associated with central lines,47 and
research in this area is accordingly active due to both the clinical implications and the
fact that Medicare and private insurers are discontinuing reimbursement for treatment
of CRBSI and hospitals are being forced to assume these costs.
Strategies for preventing CRBSIs include proper hand hygiene for providers, the use
of sterile barrier precautions for placement of central venous catheters, including skin
antiseptic preparation, early removal of catheters as soon as they are no longer
required, and routine replacement of connector tubing.45,48 Antibiotic-impregnated
catheters have also been used as a CRBSI-prevention strategy, with multiple studies
supporting their effectiveness in reducing CRBSI incidence and cost. The Institute for
Healthcare Improvement has advocated for a central-line infection prevention bundle
comprising 5 elements: optimal hand hygiene, maximal sterile barrier precautions for
catheter insertion, optimal catheter site selection, chlorhexidine skin antisepsis, and
the daily evaluation of central line necessity.49

SUMMARY

This review outlines essentials of sepsis management in the surgical patient across the
spectrum of care. Early recognition, aggressive fluid resuscitation, source control, and
antibiotic therapy result in the best possible survival for patients suffering from sepsis.
The Surviving Sepsis Guidelines should be reviewed and understood by any clinician
caring for perioperative patients. Sepsis bundles, or protocols to enact evidence-
based best practice, should be structured so that they can be implemented in a timely
fashion to improve care delivery.

REFERENCES

1. Mokdad AH, Marks JS, Stroup DF, et al. Actual causes of death in the United
States, 2000. JAMA 2004;291(10):1238–45.
2. Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United
States from 1979 through 2000. N Engl J Med 2003;348(16):1546–54.
 Essentials of Sepsis Management 363

3. Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous
oxygen saturation as goals of early sepsis therapy: a randomized clinical trial.
JAMA 2010;303(8):739–46.
4. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and
guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM
Consensus Conference Committee. American College of Chest Physicians/
Society of Critical Care Medicine. 1992. Chest 2009;136(5 Suppl):e28.
5. Bochicchio GV, Bochicchio KM, Joshi M, et al. Acute glucose elevation is highly
predictive of infection and outcome in critically injured trauma patients. Ann Surg
2010;252(4):597–602.
6. Moore LJ, McKinley BA, Turner KL, et al. The epidemiology of sepsis in general
surgery patients. J Trauma 2011;70(3):672–80.
7. Mier J, Leon EL, Castillo A, et al. Early versus late necrosectomy in severe necro-
tizing pancreatitis. Am J Surg 1997;173(2):71–5.
8. Waibel BH, Rotondo MF. Damage control for intra-abdominal sepsis. Surg Clin
North Am 2012;92(2):243–57, viii.
9. Magder SA. The highs and lows of blood pressure: toward meaningful clinical
targets in patients with shock. Crit Care Med 2014;42(5):1241–51.
10. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international
guidelines for management of severe sepsis and septic shock: 2012. Crit Care
Med 2013;41(2):580–637.
11. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment
of severe sepsis and septic shock. N Engl J Med 2001;345(19):1368–77.
12. Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign:
results of an international guideline-based performance improvement program
targeting severe sepsis. Crit Care Med 2010;38(2):367–74.
13. Ebm C, Cecconi M, Sutton L, et al. A cost-effectiveness analysis of postoperative
goal-directed therapy for high-risk surgical patients. Crit Care Med 2014;42(5):
1194–203.
14. Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid
resuscitation in the intensive care unit. N Engl J Med 2004;350(22):2247–56.
15. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion
in patients with septic shock. N Engl J Med 2008;358(9):877–87.
16. Anantasit N, Boyd JH, Walley KR, et al. Serious adverse events associated with
vasopressin and norepinephrine infusion in septic shock. Crit Care Med 2014;
42(8):1812–20.
17. Morelli A, Ertmer C, Rehberg S, et al. Phenylephrine versus norepinephrine for
initial hemodynamic support of patients with septic shock: a randomized,
controlled trial. Crit Care 2008;12(6):R143.
18. Kellum JA, M Decker J. Use of dopamine in acute renal failure: a meta-analysis.
Crit Care Med 2001;29(8):1526–31.
19. Pinsky MR, Payen D. Functional hemodynamic monitoring. Crit Care 2005;9(6):
566–72.
20. Shah MR, Hasselblad V, Stevenson LW, et al. Impact of the pulmonary artery
catheter in critically ill patients: meta-analysis of randomized clinical trials.
JAMA 2005;294(13):1664–70.
21. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with
septic shock. N Engl J Med 2008;358(2):111–24.
22. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of
hydrocortisone and fludrocortisone on mortality in patients with septic shock.
JAMA 2002;288(7):862–71.
364 Green

23. Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyper-
dynamic septic shock: a prospective, randomized, double-blind, single-center
study. Crit Care Med 1999;27(4):723–32.
24. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids in the treatment of
severe sepsis and septic shock in adults: a systematic review. JAMA 2009;
301(22):2362–75.
25. Sligl WI, Milner DA Jr, Sundar S, et al. Safety and efficacy of corticosteroids for
the treatment of septic shock: a systematic review and meta-analysis. Clin Infect
Dis 2009;49(1):93–101.
26. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of
effective antimicrobial therapy is the critical determinant of survival in human
septic shock. Crit Care Med 2006;34(6):1589–96.
27. Ibrahim EH, Sherman G, Ward S, et al. The influence of inadequate antimicrobial
treatment of bloodstream infections on patient outcomes in the ICU setting. Chest
2000;118(1):146–55.
28. Barie PS, Hydo LJ, Shou J, et al. Influence of antibiotic therapy on mortality of
critical surgical illness caused or complicated by infection. Surg Infect (Larchmt)
2005;6(1):41–54.
29. Leibovici L, Shraga I, Drucker M, et al. The benefit of appropriate empirical
antibiotic treatment in patients with bloodstream infection. J Intern Med 1998;
244(5):379–86.
30. Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the
management of candidiasis: 2009 update by the Infectious Diseases Society of
America. Clin Infect Dis 2009;48(5):503–35.
31. Garnacho-Montero J, Sa-Borges M, Sole-Violan J, et al. Optimal management
therapy for Pseudomonas aeruginosa ventilator-associated pneumonia: an
observational, multicenter study comparing monotherapy with combination
antibiotic therapy. Crit Care Med 2007;35(8):1888–95.
32. Vandijck DM, Depaemelaere M, Labeau SO, et al. Daily cost of antimicrobial therapy
in patients with Intensive Care Unit-acquired, laboratory-confirmed bloodstream
infection. Int J Antimicrob Agents 2008;31(2):161–5.
33. Tang BM, Eslick GD, Craig JC, et al. Accuracy of procalcitonin for sepsis diag-
nosis in critically ill patients: systematic review and meta-analysis. Lancet Infect
Dis 2007;7(3):210–7.
34. Heyland DK, Johnson AP, Reynolds SC, et al. Procalcitonin for reduced antibiotic
exposure in the critical care setting: a systematic review and an economic
evaluation. Crit Care Med 2011;39(7):1792–9.
35. Jensen JU, Hein L, Lundgren B, et al. Procalcitonin-guided interventions against
infections to increase early appropriate antibiotics and improve survival in the
intensive care unit: a randomized trial. Crit Care Med 2011;39(9):2048–58.
36. Hotchkiss RS, Opal S. Immunotherapy for sepsis–a new approach against an
ancient foe. N Engl J Med 2010;363(1):87–9.
37. Pipeling MR, Fan E. Therapies for refractory hypoxemia in acute respiratory
distress syndrome. JAMA 2010;304(22):2521–7.
38. Napolitano LM, Kurek S, Luchette FA, et al. Clinical practice guideline: red blood
cell transfusion in adult trauma and critical care. Crit Care Med 2009;37(12):
3124–57.
39. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled
clinical trial of transfusion requirements in critical care. Transfusion Requirements
in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med
1999;340(6):409–17.
 Essentials of Sepsis Management 365

40. Marik PE, Vasu T, Hirani A, et al. Stress ulcer prophylaxis in the new millennium: a
systematic review and meta-analysis. Crit Care Med 2010;38(11):2222–8.
41. Qaseem A, Humphrey LL, Chou R, et al. Use of intensive insulin therapy for the
management of glycemic control in hospitalized patients: a clinical practice
guideline from the American College of Physicians. Ann Intern Med 2011;
154(4):260–7.
42. Jacobi J, Bircher N, Krinsley J, et al. Guidelines for the use of an insulin infusion
for the management of hyperglycemia in critically ill patients. Crit Care Med 2012;
40(12):3251–76.
43. Moghissi ES, Korytkowski MT, DiNardo M, et al. American Association of Clinical
Endocrinologists and American Diabetes Association consensus statement on
inpatient glycemic control. Diabetes Care 2009;32(6):1119–31.
44. Aitken LM, Williams G, Harvey M, et al. Nursing considerations to complement the
Surviving Sepsis Campaign guidelines. Crit Care Med 2011;39(7):1800–18.
45. Coopersmith CM, Zack JE, Ward MR, et al. The impact of bedside behavior on
catheter-related bacteremia in the intensive care unit. Arch Surg 2004;139(2):
131–6.
46. Pronovost P, Needham D, Berenholtz S, et al. An intervention to decrease
catheter-related bloodstream infections in the ICU. N Engl J Med 2006;355(26):
2725–32.
47. Chalupka AN, Talmor D. The economics of sepsis. Crit Care Clin 2012;28(1):
57–76, vi.
48. Edgeworth J. Intravascular catheter infections. J Hosp Infect 2009;73(4):323–30.
49. Berwick DM, Calkins DR, McCannon CJ, et al. The 100,000 lives campaign:
setting a goal and a deadline for improving health care quality. JAMA 2006;
295(3):324–7.